sec-Butyl-propylacetamide Research Articles

Pharmacokinetic and pharmacodynamic analysis of (2S,3S)-sec-butylpropylacetamide (SPD) in rats and pigs-A CNS-active stereoisomer of SPD.

To advance the development of (2S,3S)-sec-butylpropylacetamide (SPD) as a new treatment for acute repetitive seizures (ARS), by studying its pharmacokinetics (PK) in pigs and its PK-pharmacodynamic (PK-PD) correlation in rats. Two (2S,3S)-SPD intramuscular formulations (FA and FB ) were administered to pigs and rats and blood samples were withdrawn at different times after dosing. Major PK parameters were estimated in both species. PD analysis was conducted in rats utilizing the maximal-electroshock seizure threshold (MEST) test. Because ARS treatment requires a rapid action, the MEST test allows comparative evaluation of (2S,3S)-SPD intramuscular injection on rat susceptibility to electroconvulsive shock at various times after dosing. In rats, (2S,3S)-SPD plasma exposure increased proportionally following intramuscular dosing (20, 25 and 40mg/kg) of FA and FB . Peak plasma concentration (Cmax ) was obtained at 1-2hours after dosing and ranged between 6.8 and 9.4mg/L. (2S,3S)-SPD plasma concentration at 10minutes after dosing (C10 ) ranged between 2.1 and 3.5mg/mL, and its half-life ranged between 0.9 and 2.3hours. The highest C10 value, which may indicate rapid activity onset, and the highest Cmax were observed following administration of FA (40mg/kg): C10 =3.5mg/L and Cmax =9.5mg/L. In the MEST test, (2S,3S)-SPD (20 and 60mg/kg) significantly raised the tonic seizure threshold compared to vehicle at 4, 7, 10, and 20minutes after dosing, with a 1.6-fold increase at 20minutes, which coincided with (2S,3S)-SPD brain Cmax . Following intramuscular dosing of (2S,3S)-SPD (12mg/kg) to pigs of FA and FB , a Cmax value of 0.9mg/L was obtained 0.42 and 0.75hours after dosing, respectively. (2S,3S)-SPD C10 was 0.27mg/L (FA ) and 0.49mg/L (FB ). (2S,3S)-SPD clearance, volume of distribution, and half-life were 2L/h/kg, 18-28L/kg, and 6.1-9.7hours, respectively. (2S,3S)-SPD demonstrated a good PK-PD correlation in the rat MEST test, with a rapid onset. (2S,3S)-SPD first PK study in pigs showed that doses >12mg/kg are required to achieve in pigs the plasma concentrations associated with activity at the rat MEST test.

Novel treatment approaches and pediatric research networks in status epilepticus

This paper contains five contributions which were presented as part of the novel therapies section of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures. These illustrate recent advances being made in the management and therapy of status epilepticus. The five contributions concern: genetic variations in Na + channel genes and their importance in status epilepticus; the European Reference Network for rare and complex epilepsies EpiCARE; the North American Pediatric Status Epilepticus Research Group (pSERG); Fenfluramine as a potential therapy for status epilepticus’ and the valproate derivatives, valnoctamide and sec-butylpropylacetamide (SPD), as potential therapies for status epilepticus.This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures”

Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase.

The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues. While the pyruvate and 2-oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 µM. Among the reactions involved in pyruvate oxidation, pyruvate transport and dehydrogenation steps were not affected by VPA, while α-lipoamide dehydrogenase was strongly inhibited. Strong inhibition of α-lipoamide dehydrogenase was also noted for the VPA one-carbon homolog sec-butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec-butylpropylacetamide (SPD) and valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD, show low inhibitory effects on mitochondrial oxidative phosphorylation in the liver, which might be relevant for treatment of patients with mitochondrial epilepsy.

Sec-Butylpropylacetamide (SPD), a new amide derivative of valproic acid for the treatment of neuropathic and inflammatory pain

Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world’s population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study, we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan, and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD’s activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.

Sec-Butylpropylacetamide (SPD) has antimigraine properties.

Though migraine is disabling and affects 12%-15% of the population, there are few drugs that have been developed specifically for migraine prevention. Valproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that is also used for migraine prophylaxis, but its clinical use is limited by its side effect profile. sec-Butylpropylacetamide (SPD) is a novel VPA derivative, designed to be more potent and tolerable than VPA, that has shown efficacy in animal seizure and pain models. We evaluated SPD's antimigraine potential in the cortical spreading depression (CSD) and nitroglycerin (NTG) models of migraine. To evaluate SPD's mechanism of action, we performed whole-cell recordings on cultured cortical neurons and neuroblastoma cells. In the CSD model, the SPD-treated group showed a significantly lower median number of CSDs compared to controls. In the NTG-induced mechanical allodynia model, SPD dose-dependently reduced mechanical sensitivity compared to controls. SPD showed both a significant potentiation of GABA-mediated currents and a smaller but significant decrease in NMDA currents in cultured cortical neurons. Kainic acid-evoked currents and voltage-dependent sodium channel currents were not changed by SPD. These results demonstrate SPD's potential as a promising novel antimigraine compound, and suggest a GABAergic mechanism of action.

Pharmacokinetic–Pharmacodynamic Correlation and Brain Penetration of sec-Butylpropylacetamide, a New CNS Drug Possessing Unique Activity against Status Epilepticus

sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of the ability to block SE when given 20-60 min after the beginning of a seizure. However, intraperitoneal (i.p.) administration to rats cannot be extrapolated to humans. Consequently, in the current study a comparative pharmacokinetic (PK)-pharmacodynamic analysis of SPD was conducted following i.p., intramuscular (i.m.), and intravenous (i.v.) administrations to rats. SPD brain and plasma levels were quantified at various times after dosing following i.p. (60 mg/kg), i.v. (60 mg/kg), and i.m. administrations (120 mg/kg) to rats, and the major PK parameters of SPD were estimated. The antiseizure (SE) efficacies of SPD and its individual stereoisomers were assessed in the pilocarpine-induced BZD-resistant SE model following i.p. and i.m. administrations to rats at 30 min after seizure onset. The absolute bioavailabilities of SPD following i.p. and i.m. administrations were 76% (i.p.) and 96% (i.p.), and its clearance and half-life were 1.8-1.5 L h(-1) kg(-1) and 0.5-1.7 h, respectively. The SPD brain-to-plasma AUC ratios were 1.86 (i.v.), 2.31 (i.p.), and 0.77 (i.m.). Nevertheless, the ED50 values of SPD and its individual stereoisomers were almost identical in the rat pilocarpine-induced SE model following i.p. and i.m. administrations. In conclusion, in rats SPD is completely or almost completely absorbed after i.m. and i.p. administration and readily penetrates into the brain. Consequently, in spite of PK differences, the activities of SPD in the BZD-resistant SE model following i.m. and i.p. administrations are similar.

The potential of sec-butylpropylacetamide (SPD) and valnoctamide and their individual stereoisomers in status epilepticus.

sec-Butylpropylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide--valpromide. Racemic-SPD and racemic-VCD possess a unique and broad-spectrum antiseizure profile superior to that of VPA. In addition, SPD blocks behavioral and electrographic status epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon. Valnoctamide has similar activity as SPD in the soman-induced SE model. The activity of SPD and VCD against SE is superior to that of diazepam and midazolam in terms of rapid onset, potency, and ability to block SE when given 20 to 60 min after seizure onset. sec-Butylpropylacetamide and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four individual stereoisomers. The anticonvulsant activity of the individual stereoisomers of SPD and VCD was comparatively evaluated in several anticonvulsant rodent models including the benzodiazepine-resistant SE model. sec-Butylpropylacetamide has stereoselective pharmacokinetics (PK) and pharmacodynamics (PD). The higher clearance of (2R,3S)-SPD and (2S,3R)-SPD led to a 50% lower plasma exposure and, consequently, to a lower anticonvulsant activity compared to racemic-SPD and its two other stereoisomers. Racemic-SPD, (2S,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (2S,3R)-SPD. Valnoctamide has a stereoselective PK with (2S,3S)-VCD exhibiting the lowest clearance and, consequently, a twice-higher plasma exposure than all other stereoisomers. Nevertheless, there was less stereoselectivity in VCD anticonvulsant activity, and each stereoisomer had similar ED50 values in most models. sec-Butylpropylacetamide and VCD stereoisomers did not cause teratogenicity (i.e., neural tube defect) in mice at doses 3-12 times higher than their anticonvulsant-ED50 values. This article is part of a Special Issue entitled "Status Epilepticus".

Pharmacodynamic and pharmacokinetic analysis of CNS-active constitutional isomers of valnoctamide and sec-butylpropylacetamide — Amide derivatives of valproic acid

Valnoctamide (VCD) and sec-butylpropylacetamide (SPD) are CNS-active closely related amide derivatives of valproic acid with unique anticonvulsant activity. This study evaluated how small chemical changes affect the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and pharmacokinetics (PK) of three constitutional isomers of SPD [sec-butylisopropylacetamide (SID) and tert-butylisopropylacetamide (TID)] and of VCD [tert-butylethylacetamide (TED)]. The anticonvulsant activity of SID, TID, and TED was comparatively evaluated in several rodent anticonvulsant models. The PK–PD relationship of SID, TID, and TED was evaluated in rats, and their teratogenicity was evaluated in a mouse strain highly susceptible to teratogen-induced neural tube defects (NTDs). sec-Butylisopropylacetamide and TID have a similar PK profile to SPD which may contribute to their similar anticonvulsant activity. tert-Butylethylacetamide had a better PK profile than VCD (and SPD); however, this did not lead to a superior anticonvulsant activity. sec-Butylisopropylacetamide and TED did not cause NTDs at doses 4–7 times higher than their anticonvulsant ED50 values. In rats, SID, TID (ip), and TED exhibited a broad spectrum of anticonvulsant activity. However, combined anticonvulsant analysis in mice and rats shows SID as the most potent compound with similar activity to that of SPD, demonstrating that substitution of the isobutyl moiety in the SPD or VCD molecule by tert-butyl as well as a propyl-to-isopropyl replacement in the SPD molecule did not majorly affect the anticonvulsant activity.

Sec-Butyl-propylacetamide (SPD) and two of its stereoisomers rapidly terminate paraoxon-induced status epilepticus in rats.

Organophosphates (OPs) are commonly used insecticides for agriculture and domestic purposes, but may also serve as nerve agents. Exposure to OPs result in overstimulation of the cholinergic system and lead to status epilepticus (SE), a life-threatening condition that is often resistant to treatment. SE is associated with significant neuronal damage, neurocognitive dysfunction, and the development of lifelong epilepsy. Therefore, rapid termination of SE and prevention of brain damage is of high interest. Here we tested the efficacy of sec-butyl-propylacetamide (SPD) and two of its individual stereoisomers, (2S,3S)-SPD and (2R,3R)-SPD, in discontinuing OP-induced seizures. SPD is a one carbon homolog of valnoctamide, a central nervous system (CNS)-active constitutional isomer of valproic acid (VPA) corresponding amide valpromide. Rats were implanted with epidural telemetric electrodes to allow electrocorticography (ECoG) recording 24 h prior, during and 24 h after poisoning with the OP paraoxon (at a dose equivalent to 1.4 LD50 Median lethal dose). All rats were provided with antidotal treatment of atropine and toxogonin. Epileptic activity was measured using a novel automated system to evaluate the different effects of midazolam, SPD, and its individual stereoisomers in comparison to nontreated controls. Treatment with SPD or its individual stereoisomer (2S,3S)-SPD significantly shorten paraoxon-induced SE and reduced the duration of recorded pathologic activity after SE was terminated. (2S,3S)-SPD was superior to racemic-SPD in diminishing delayed pathologic epileptiform activity within the first 8 h after SE. These results suggest SPD as an efficient drug for the rapid termination of SE and pathological epileptiform activity following OP poisoning, a strategy to reduce neuronal dysfunction and the risk for lifelong epilepsy.

Valnoctamide and sec‐butyl‐propylacetamide (SPD) for acute seizures and status epilepticus

sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. VCD has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain, and is currently being developed for the treatment of bipolar disorder. Both VCD and SPD possess two stereogenic carbons in their chemical structure. SPD possesses a unique and broad-spectrum antiseizure profile superior to that of valproic acid (VPA) and better than that of VCD. In addition SPD blocked behavioral- and electrographic-SE induced by pilocarpine and soman (organophosphate nerve gas) and afforded in vivo neuroprotection that was associated with cognitive sparing. VCD has activity similar to that of SPD in pilocarpine-induced status epilepticus (SE), although at higher doses. The activity of SPD and VCD against SE is superior to that of diazepam in terms of rapid onset, potency, and ability to block SE when given 20-60min after seizure onset. When administered 20 and 40min after SE onset, SPD (100-174mg/kg) produced long-lasting efficacy (e.g., 4-8h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD activity in the pilocarpine and soman-induced SE models when administered 20-60min after seizure onset, differentiates SPD from benzodiazepines and all other antiepileptic drugs .

Valproic acid derivatives signal for apoptosis and repair in vitro

PurposeTo determine the cytotoxicity of valproic acid (VPA) and its derivatives in human hepatoblastoma (HepG2) cells, and to study the possible toxicity of these compounds in human lymphocytes from patients with known hypersensitivity syndrome reactions (HSRs) to other medication. MethodsCells were exposed to physiological doses of VPA, valnoctamide (VCD) and its one carbon homologue sec-Butyl-propyl-acetamide (SPD) for 2h and for 24h. Cell viability was measured using succinate dehydrogenase activity for hepatocytes and lymphocyte toxicity assay (LTA) for lymphocytes. Cytokines and apoptosis [cytokeratine 18 (cCK18-M30)] markers were quantitated by ELISA. ResultsVCD and SPD presented lower cytotoxicity compared to VPA in cultured HepG2 cells. SPD led to cytotoxicity in lymphocytes. VPA and its derivatives increased the release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in media, but had no influence on the release of either interleukin (IL)-1 or IL-6. Significant increases in the release of IFN-γ and TNF-α were observed in lymphocytes exposed to high doses of VPA, and this increased further with exposure time. SignificanceHepG2 cells exposed to VCD and SPD experienced lower direct cytotoxicity than those treated with VPA. Lymphocytes from patients that experienced HSR to other medication have shown cytotoxicity to VPA and its VPA derivatives-induced. High levels of pro-inflammatory cytokines were released in the cell culture media, suggesting that inflammation plays a key role in VPA-derivatives induced lymphocyte toxicity.

A comparative electrographic analysis of the effect of sec-butyl-propylacetamide on pharmacoresistant status epilepticus

Better treatment of status epilepticus (SE), which typically becomes refractory after about 30min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electroencephalograms (EEGs) were recorded from rats during ESE induced with lithium-pilocarpine. Using a previously-published algorithm, the effects of SPD on ESE were compared quantitatively to other relevant compounds. To confirm benzodiazepine resistance, diazepam (DZP) was shown to suppress ESE when administered 15min after the first motor seizure, but not after 30min (100mg/kg). VPA (300mg/kg) also lacked efficacy at 30min. SPD (130mg/kg) strongly suppressed ESE at 30min, less after 45min, and not at 60min. At a higher dose (180mg/kg), SPD profoundly suppressed ESE at 60min, similar to propofol (100mg/kg) and pentobarbital (30mg/kg). After 4–6h of SPD-induced suppression, EEG activity often overshot control levels at 7–12h. Valnoctamide (VCD, 180mg/kg), an SPD homolog, was also efficacious at 30min. SPD blocks pilocarpine-induced electrographic seizures when administered at 1h after the first motor seizure. SPD has a faster onset and greater efficacy than DZP and VPA, and is similar to propofol and pentobarbital. SPD and structurally similar compounds may be useful for the treatment of refractory ESE. Further development and use of automated analyses of ESE may facilitate drug discovery for refractory SE.

A new derivative of valproic acid amide possesses a broad‐spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage

sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death. The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6-Hz psychomotor; subcutaneous (s.c.) metrazol-, s.c. picrotoxin, s.c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post-SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model. SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD(50)/ED(50)]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED(50) for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpine-induced SE. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED(50) values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK-PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman-induced seizures) and 12-50 mg/L (40 min after the onset of soman-induced seizures). The time to peak (t(max)) pharmacodynamic effect (PD-t(max)) occurred after the PK-t(max), suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD. The results demonstrate that SPD is a broad-spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement.